This study is an evaluation of the dosing patterns of ustekinumab among patients with psoriasis in a real-world setting.
Psoriasis—a chronic, inflammatory skin disease affecting approximately 2.2% of the US population—is considered the most prevalent immune-mediated inflammatory disease.1,2 Approximately 80% of patients with psoriasis have mild to moderate disease, whereas the remaining 20% have moderate to severe disease.3 Mild psoriasis involves itching and burning on affected parts of the body, while severe psoriasis is also frequently associated with joint pain or arthritis.3-6 As a multisystemic disorder, psoriasis is frequently associated with a number of comorbid conditions, including psoriatic arthritis, cardiovascular disorders, hypertension, dyslipidemia, metabolic syndrome, obesity, and diabetes. 7-11 Notably, due to skin lesions, patients with psoriasis also often experience significant psychological comorbidities, such as anxiety and depression.12,13
There is no available cure for psoriasis; therefore, various lines of therapies are used to alleviate disease symptoms, reduce or clear plaques, and induce remission.14 Conventional therapies, including topical agents, phototherapy (such as psoralen plus ultraviolet A or ultraviolet B), and systemic medications (such as methotrexate, retinoids, or cyclosporine) have been used as the mainstay treatments of psoriasis. However, previous studies have shown that, for some patients, these therapies may be limited in the long term due to adverse events (AEs).3,15,16 With the increased understanding of the immunology of psoriasis, biologics have emerged as an alternative option with significant impact on providing long-term continuous psoriasis control by interfering with T cell function, by inhibiting tumor necrosis factor-α, or by selectively targeting interleukin-12 (IL-12) and IL-23.3,16,17 The American Academy of Dermatology (AAD) guidelines recommend biologics in the management of psoriasis when 1 or more conventional systemic medications are not tolerated due to AEs, are unsuitable due to comorbidities, or fail to produce an adequate response.3,16 Furthermore, the most recent AAD guidelines emphasize that biologics have no relevant drug interactions and have fewer significant safety issues compared with conventional systemic agents; they also highlight the benefits of biologic treatments for patients with complex medical and dermatologic histories on various medications.16
Ustekinumab, as the first agent to inhibit IL-12/23, is a novel biologic. It was approved by the FDA in September 2009 for the treatment of moderate to severe psoriasis,18 and has also been recently recommended as a first-line systemic treatment specifically for patients with chronic plaque psoriasis.16,19 The dose of ustekinumab is determined on the basis of patient weight. For patients weighing 100 kg (220 lb) or less, the recommended dose is 1 initial 45-mg dose followed by another dose 4 weeks later, then another 45-mg dose every 12 weeks thereafter. For patients weighing more than 100 kg (220 lb), the recommended dose is 1 initial 90-mg dose followed by another dose 4 weeks later, then a 90-mg dose every 12 weeks thereafter. It is worth noting that 45-mg ustekinumab was also shown to be efficacious in patients weighing more than 100 kg; however, 90-mg ustekinumab resulted in greater efficacy in these patients.18 Clinical trials have demonstrated the safety and efficacy of ustekinumab in improving the symptoms of psoriasis.20-23 Recently published 5-year efficacy and safety results demonstrate the long-term response associated with ustekinumab as well as the lack of any dose-related or cumulative toxicity with increasing duration of ustekinumab exposure for up to 5 years.24,25 Additionally, results from a phase 3, doubleblind trial have shown that the efficacy of ustekinumab was superior to that of etanercept in patients with psoriasis. 26,27 Despite these positive findings on the efficacy and safety of ustekinumab in clinical trials, limited studies are available to quantify the real-world utilization and dosage patterns of ustekinumab. The main objective of this study was to assess the characteristics and dosing patterns of patients with psoriasis initiated on ustekinumab therapy using a large retrospective administrative claims database.
This retrospective analysis used patient-level data from the HealthCore Integrated Research Database (HIRD, HealthCore Inc, Wilmington, DE). HIRD includes longitudinal claims data from 14 geographically dispersed health plans in the United States, covering approximately 44 million insured lives at the time this study was conducted. HIRD consists of integrated medical claims, pharmacy claims, and eligibility files. All study data were de-identified and developed in compliance with the Health Insurance Portability and Accountability Act. It was determined that a waiver of informed consent from an institutional review board was not required to conduct this study.
The study population consisted of patients 18 years or older who received ustekinumab and had at least 1 medical claim for psoriasis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9- CM] code of 696.1x) during the study period of September 1, 2009, through November 30, 2010. Ustekinumab was identified from medical claims using the Healthcare Common Procedure Coding System code C9261, or any of the following National Drug Codes ([NDCs]: 57894006002, 57894006003, 57894006103) from pharmacy claims. The date of the first medical or pharmacy claim for ustekinumab was designated as the index date.
All patients included in the analysis were required to have at least 12 months of continuous health plan enrollment prior to the index date. Due to the recent availability of ustekinumab and its early uptake at the time of the study, limited follow-up data were available for the study patients. Therefore, no minimum follow-up period was required and variable follow-up was allowed; however, patients were followed through the latest date of their continuous eligibility after the index date. Patients were excluded from the study if they had a claim for another biologic (ie, adalimumab, alefacept, etanercept, or infliximab) on the index date (
Patient Characteristics. Patient characteristics were evaluated during 12 months prior to the index date. Demographic characteristics included age, gender, geographic region (as determined by the US Census classification), and type of health insurance plan (preferred provider organization [PPO], health maintenance organization [HMO], or other insurance plan type). Patients’ comorbidity burden was measured using the Deyo-Charlson Comorbidity Index (DCI)28 and specific psoriasis-related comorbid conditions during the pre-index period. The DCI consists of 19 diagnoses identified by ICD-9-CM codes, with a scoring weight from 1 to 6 identified for each diagnosis. The final summary DCI score consists of a sum of weighted values for existing comorbidities, ranging from 0 to 33, with higher scores indicating a greater comorbidity burden. Additionally, the use of various psoriasis- related treatments during the 12-month pre-index period was assessed. Pre-index all-cause and psoriasisrelated healthcare resource utilization and costs, including inpatient admissions, emergency department (ED) visits, physician office visits, and pharmacy fills, were presented. Pre-index costs were calculated using health plan allowed amounts, which are the full fees contractually allowed by health plans (inclusive of the amount paid by the health plan and the patient), and were adjusted for 2010 dollars using the medical care consumer price index from the Bureau of Labor Statistics.29
Ustekinumab Dosing Patterns. Observing ustekinumab dosing patterns required methodological considerations as a result of how the drug was packaged and supplied after FDA approval, while accounting for typical reimbursement and practice patterns. Initially, a 45-mg ustekinumab vial could be used in patients with either dose requirement, whereby a patient requiring a 45-mg dose would be prescribed 1 vial and a patient requiring a 90-mg dose would be prescribed 2 vials. The 45-mg vial was subsequently replaced by 45-mg and 90-mg prefilled syringes (PFSs) in February 2010, allowing for more convenient administration options. Preliminary analyses conducted by the authors found that health plans would reimburse for the first 2 doses of ustekinumab in a single prescription. Indicators in the administrative claims of this type of reimbursement practice included the cost of the fill and the time interval between fills.
In determining the index ustekinumab dose, patients with a single claim of 45-mg or 90-mg PFSs were categorized as having received the 45-mg or 90-mg dose, respectively. For patients who had a second fill within 98 to 125 days (ie, 16 weeks ± 2 weeks) between the index date and the next fill date, the index dose was determined using the wholesale acquisition cost ± 15% along with the allowed cost amounts in the claims. For these patients, the second fill was coded as the third dose to account for the first claim including doses 1 and 2, and all subsequent doses were recoded forward thereafter. For all other patients, second and third doses were determined by the dose shown in the claim.
Intervals between fills were calculated as the days between observed ustekinumab fills. Interval patterns were assessed based on a window around the recommended fill intervals per prescribing information (ie, 28 ± 7 days for the interval of index to second dose, and 84 ± 14 days for interval of second and third dose). Patients were then categorized as having fills “expected,” “later than expected,” or “earlier than expected” by comparing the observed fill intervals against the FDA label-recommended fill intervals.
Statistical Analyses. Descriptive statistics were calculated for all study measures and outcomes. Mean (± SD) and median were calculated for continuous variables and frequency (percentage) was used for categorical variables. All the statistical analyses were conducted using SAS Version 9.1 (SAS Institute, Inc, Cary, North Carolina).
Of the 563 patients with at least 1 medical or pharmacy claim for ustekinumab during the study period, 374 met all study criteria and were included in the analysis (
). The mean (± SD) age was 48.0 (± 11.9) years, 43.6% were female, and 74.9% were primarily covered by PPO health insurance plans (
). Approximately 70% of the study patients resided in the West and Southeast regions of the United States. On average, study patients had a 6-to-7- month follow-up period with a median of 209 follow-up days after the index fill.
At baseline, the mean DCI score was 0.6 (SD ± 0.9), indicating low burden of comorbid conditions. The most commonly occurring comorbid conditions were dyslipidemia (46.3%), hypertension (43.3%), psoriatic arthritis (22.2%), diabetes (16.3%), and anxiety (12.0%). A total of 217 patients (58.0%) used topical steroids during the pre-index period while 36.4% used non-biologic systemic medications (Table 1). Methotrexate (19.3%) and prednisone (13.1%) were the most commonly administered nonbiologic systemic medications.
In terms of healthcare resource utilization, about 9.1% of study patients had at least 1 hospital admission for any cause within the 12-month pre-index period before receiving ustekinumab (Table 1), for which the average length of stay was 4 days. A few patients (2.7%) had 1 or more psoriasis-related hospital admission, with an average length of stay of 3 days, and only 7 patients (1.9%) had 1 or more psoriasis-related ED visit during the preindex period. Within the pre-index period, study patients had an average of 10 all-cause physician office visits and 4 psoriasis-related physician office visits. During the preindex period, the average all-cause costs were $22,495 (± $19,978) and the average psoriasis-related costs were $17,560 (± $26,031), more than half of which were due to prescriptions.
The majority of study patients (69.5%) used at least 1 biologic agent prior to ustekinumab initiation. Of those with pre-index biologic experience, 22.3% had a history of using 2 or more biologics. Adalimumab and etanercept were the most frequently used biologics, with 38.8% and 40.0% of the biologic-experienced patients, respectively, using them immediately prior to initiating ustekinumab (
). In addition, the average time lapse between the last etanercept fill and the index ustekinumab fill was 77.5 days (± 74.3); similarly, the time lapse between the last adalimumab fill and the index ustekinumab fill was 76.8 days (± 85.2).
Ustekinumab Dosing Patterns
In the analysis of ustekinumab dosing patterns, all patients who met the study criteria of having 1 fill or more for ustekinumab were included. Overall, 83.8% (284 of 339 who were followed up for 4 weeks or more) of patients had a second ustekinumab fill and 87.7% (207 of 236 who were followed up for 16 weeks or more) had a third ustekinumab fill after the index fill. On the index date, most patients (n = 294, 78.6%) received a 45-mg ustekinumab dose while the remaining 80 patients (21.4%) received a 90-mg dose (
). During the postindex period, the majority of the study patients remained on the 45-mg dose of ustekinumab, although a few patients switched to a 90-mg dose. Specifically, at the time of the second fill, 8 of 284 patients (2.8%) received a higher dose and only 1 patient received a lower dose than their index dose. By the third fill, 13 of 207 patients (6.9%) received a higher ustekinumab dose, while 5 patients (2.7%) received a lower dose than their previous fill. The median number of days was 28 days between the index and the second ustekinumab fill, and 85 days between the second and the third ustekinumab fills (Table 3). These findings are very much in line with the recommended dosing regimen for ustekinumab, in that the second dose should be administered 4 weeks (28 days) after the first dose and the following doses should be administered every 12 weeks (84 days) thereafter.
Among patients with a second ustekinumab fill (n = 284), most patients (70.1%) had their second prescription filled as expected (within 21-35 days of index fill). Fewer patients (4.2%) got their second fill earlier than expected, while 25.7% had it filled later than expected (
). Among patients with a third ustekinumab fill (n = 207), 75.9% had their third prescription filled as expected (within 71-97 days from the date of the second fill), while the rest had their third filled earlier (8.7%) or later (15.4%) than expected.
This is the first study to provide real-world evidence of the demographic and clinical characteristics, as well as the treatment patterns, of patients with psoriasis who were initiated on ustekinumab. Specifically, this study described the observed dosage patterns of ustekinumab in a large managed care population in the United States.
Results from this study show that approximately 69.5% of patients used at least 1 type of biologic agent, 58.0% used topical steroids, and 36.4% used nonbiologic systemic treatments prior to ustekinumab initiation. Among those who had received other biologics prior to receiving ustekinumab, the majority (78.9%) had used etanercept or adalimumab as the most recent biologic agent, and the average time between switching from etanercept or adalimumab to ustekinumab was quite similar (about 77 days). Previous studies present mixed evidence for patients with psoriasis who were treated with systemic therapy. For example, a claims study found that only 3.1% of patients had used biologic therapy and more than 30% had used 1 type of systemic therapy.30 On the other hand, a survey study31 found that only 26% of respondents had used systemic medication, phototherapy, or both, and 35% received only topical therapy. Consistent with results from another psoriasis administrative claim—based study,32 this study found that dyslipidemia and hypertension were the 2 most prevalent comorbidities for patients with psoriasis. Diabetes, anxiety, and depression were found at baseline in more than 10% of patients in the current study.
This study found that approximately 78.6% of the patients were initiated at a 45-mg dose on the index date and the remaining patients (21.4%) received 90-mg ustekinumab. Fewer than 7% of patients had an increased dose at the third fill, in contrast to a nearly 3% of patients receiving a decreased dose at the third fill. This study also showed that most patients had their second and third prescriptions filled as expected, per the recommended dosing schedule. When ustekinumab was not filled as expected after the index fill, 50.7% and 78.1% had their second and third ustekinumab, fill, respectively, within 30 days of the recommended schedule date.
Information on treatment adherence is important because better treatment adherence has been associated with decreased healthcare resource utilization and decreased other costs for many chronic diseases such as diabetes,33 hypertension,34 and multiple sclerosis.35 Although this study did not assess adherence or persistency of ustekinumab due to a limited sample size and follow-up time, this study demonstrated that the majority of patients had their second (83.8%) and third (87.7%) ustekinumab prescriptions filled within the expected time frame, suggesting that adherence with ustekinumab may be promising. However, this hypothesis needs to be confirmed with further research, at which time it would also be worthwhile to examine ustekinumab treatment adherence and the associated economic benefit of adherence among patients with psoriasis.
This study was subject to a few limitations inherent in analyses of retrospective claims data. The existence of a pharmacy claim for a filled prescription does not guarantee that the medication was actually used by the patient, nor does it indicate that the medication was taken as prescribed. Administrative claims data do not typically include clinical data to assist with inferring the effectiveness of a treatment (such as ustekinumab in this study). Study results were derived from a database of members of large commercial health plans in the United States; therefore, results may not be generalizable to people with other types of insurance or those who reside outside the United States. Nonetheless, the data used in this study were derived from a large, geographically diverse population, which enhances the generalizability of the results. In addition, the scope of this study was intended to represent initial ustekinumab dosing patterns, and therefore the results should not be generalized for longer-term maintenance use of the drug.
The findings from this study can offer data to health plans regarding the characteristics of patients with psoriasis who were initiated on ustekinumab. As the first study to investigate the utilization patterns of ustekinumab in a large US managed care population, this study provides insights on the real-world dosage patterns and fill intervals of ustekinumab. The majority of patients with psoriasis in this study received fills per the recommended administration schedule at the 45-mg dose with very few changes in dose following the index administration. Results on ustekinumab dosage and fill patterns have important implications in estimating the cost of ustekinumab from the perspective of healthcare payers. These results may be incorporated in health plan utilization reviews, may be used as part of indirect comparisons with existing data for other biologics, and may offer payers a path to treatment cost predictability.